Intake of Sucrose-sweetened Water Induces Insulin Resistance and Exacerbates Memory Deficits and Amyloidosis in a Transgenic Mouse Model of Alzheimer Disease

Abstract

Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote ADlike pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2-3-fold increase in insoluble amyloid-␤ protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-␤ precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of A␤, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.Added sugars, mainly sucrose and high fructose corn syrup, are major components of a modern human diet. Compelling evidence indicates that excess consumption of sweet foods, particularly sugar-sweetened beverages, plays an important role in the epidemic of obesity around the world (1). In the United States, the percentage of children who are overweight has doubled, and the percentage of teenagers who are overweight has tripled (2, 3). Overweight children are at an increased risk to become obese adults (4). Even moderate obesity can contribute to chronic metabolic abnormalities leading to type 2 diabetes mellitus (5) characterized by glucose intolerance and hyperinsulinemia.Alzheimer disease (AD) 2 is a progressive neurodegenerative disease characterized clinically by progressive cognitive impairment. Pathological hallmarks of the AD brain include intracellular neurofibrillary tangles and deposits of aggregated amyloid-␤ protein (A␤) in neuritic plaques and cerebral vessels. The pathogenic mechanisms that lead to the development of AD, however, are not fully understood. One of the main hypotheses is that ␤-amyloidosis (production and deposition of A␤) plays a crucial role in the pathogenesis of AD (6). A␤ (39 -43 amino acids) is derived from a large transmembrane glycoprotein, amyloid-␤ precursor protein (APP), via proteolytic processing by secretases (6). This hypothesis is supported by discoveries of...

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…type 2 diabetes. Indeed, our HFD study is in agreement with a similar study using sucrose-rich diet (10% sucrose) as a dietary supplement, which also led to an increase in body weight gain in APP/PSEN1 mice [27]; however, that study only used non-supplemented diet vs supplemented diet in APP/PSEN1 mice. No wild-type or transgene alone mice were included for a comparison.…”

“…Alzheimer's disease is the most common form of dementia, characterised by loss of recent memory as one of the first symptoms and a progressive decline in all cognitive skills later on in the disease [3,26]. Considerable evidence suggests that insulin resistance and obesity may directly contribute to the pathogenesis of Alzheimer's disease [27][28][29][30][31]. However, not much emphasis has been put on the role of Alzheimer's disease in obesity and type 2 diabetes development, as characterised by insulin resistance.…”

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

“…During visible platform testing (learning phase), all mice showed similar learning latencies (Supplementary Figure S2B), indicating that NTI or β-FNA treatment had little effect on the vision, motor ability or motivation of the mice. However, as shown in Figure 4A, during hidden platform testing, APP/PS mice showed a significantly slower learning rate compared with the transgene-negative littermates (P = 0.007), indicating consistent learning and memory deficits of APP/PS mice, as reported previously [59]. Interestingly, chronic NTI treatment, but not β-FNA treatment, reversed the spatial learning and memory impairment of APP/PS mice (P < 0.001 APP/PS NTI-treated mice versus APP/PS control mice; P = 0.507 APP/PS NTI-treated mice versus transgene-negative mice; P = 0.309 APP/PS β-FNA-treated mice versus APP/PS control mice, Figure 4A).…”

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

“…Conversely, insulin-resistant type 2 diabetes patients show significantly increased risk for developing AD (31). Moreover, experimental induction of diabetes in mouse models of AD results in premature cognitive failure and degeneration of synapse structure (32,33).…”